Fused bicyclic pyridine derivatives as tachykinin receptor antagonists

ABSTRACT

A novel fused bicyclic pyridine derivative or a salt thereof that acts as a tachykinin receptor antagonist, in particular as an NK1 receptor antagonist, is represented by the following general formula (1):  
                 
wherein the rings A and B are each a benzene ring which may have 1 to 3 substituents (any adjacent two of which may be bound to one another to form a ring); the ring C is a nitrogen-containing ring having a hydrogen atom substituted with a nitrogen atom; 
         R 1  and R 2  are each independently a hydrogen atom, a C 1  to C 6  alkyl group, a C 1  to C 6  alkylsulfonyl group, a C 1  to C 6  alkylcarbonyl group, or a C 1  to C 6  alkoxycarbonyl group, or R 1  and R 2  are bound to one another to form the ring D; m is 1 or 2; n is 2 or 3; and q is an integer from 1 to 4.

TECHNICAL FIELD

The present invention relates to novel fused bicyclic pyridinederivatives that act as tachykinin receptor antagonists, as well as topharmaceutically acceptable salts, hydrates, and solvates thereof. Thepresent invention also relates to pharmaceutical use of such compounds.

TECHNICAL BACKGROUND

‘Tachykinin’ is a collective term for such neuropeptides as substance P,neurokinin A, and neurokinin B. Tachykinins are known to exhibit variousphysiological activities by binding to respective receptors (neurokinin1 (NK1), neurokinin 2 (NK2), and neurokinin 3 (NK3)) present in a humanbody. Of different tachykinins, substance P, aside from its role as aneurotransmitter in primary sensory neurons in central and peripheralnervous systems, brings about various physiological effects, such asdiuresis, excitation of neurons, increased blood vessel permeability,blood vessel dilation, contraction of smooth muscles, and immuneactivities. Substance P is also believed to play significant roles inthe onset of various pathological conditions, such as pollakiuria,incontinence, vomiting, inflammation, allergies, respiratory tractdisorders, pains, and central nervous system disorders. Accordingly, aneed exists for the development of a compound that acts as a tachykininreceptor antagonist, in particular as an NK1 receptor antagonist, and istherefore suitable for use as an effective prophylactic or therapeuticagent against various pathological conditions such as those mentionedabove. It is also desired that such a compound offer high safety,persistence of efficacy, and other advantageous characteristics.

At present, the following compounds are known as NK1 receptorantagonists and are described in the following publications:(1) European Patent Application Publication No. EP-A-429366 describescompounds such as the one represented by the following formula:

(2) International Patent Publication No. WO91/09844 describes compoundssuch as the one represented by the following formula:

(3) European Patent Application Publication No. EP-A-532456 describescompounds such as the one represented by the following formula:

(4) European Patent Application Publication No. EP-A-522808 describescompounds such as the one represented by the following formula:

(5) International Patent Publication No. WO93/01169 describes compoundssuch as the one represented by the following formula:

(6) Japanese Patent Laid-Open Publication No. Hei 8-67678 describes acompound represented by the following formula and salts thereof:

wherein the rings A and B are each a homocyclic or heterocyclic ringwith at least one of the rings A and B being a heterocyclic ring; thering C is a benzene ring; R is H or a hydrocarbon residue; one of X andY is —NR¹— (where R¹ is H or a hydrocarbon residue) or —O— and the otheris —CO— or —CS—, or one of X and Y is —N═ and the other is ═CR²— (whereR² is H, a halogen, a hydrocarbon residue, an amino or a hydroxylgroup); and n is 1 or 2.(7) Japanese Patent Laid-Open Publication No. Hei 9-104674 describes acompound represented by the following formula:

wherein X is a hydrogen or oxygen atom; Y is a nitrogen or oxygen atomwhich may or may not be alkylated or acylated; R¹ is a hydrogen atom, alower alkyl group, a lower alkanoyl group, an alkyl group containing anitrogen atom, a carbamoyl group, a lower alkylthio group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, or a(4-phenylpiperadine-1-yl)methyl group; R² is a hydrogen atom, a loweralkyl group, a lower alkyl group containing a hydroxyl group, a loweralkanoyl group, or a lower alkoxy group; and the rings A and B are eacha substituted or unsubstituted benzene ring.(8) Japanese Patent Laid-Open Publication No. Hei 9-263585 describes acompound represented by the following formula:

wherein the ring M is a heterocyclic ring in which the structural moiety—X═Y< is —N═C<, —CO—N<, or —CS—N<; Ra and Rb may together form the ringA, or Ra and Rb are each independently a hydrogen atom or a substituentof the ring M; the rings A and B are each independently a substituted orunsubstituted homocyclic or heterocyclic ring, provided that at leastone of the rings A and B is a substituted or unsubstituted heterocyclicring; the ring C is a substituted or unsubstituted homocyclic orheterocyclic ring; the ring Z is a substituted or unsubstituted ring;and n is an integer from 1 to 6.(9) Japanese Patent Laid-Open Publication No. Hei 11-246559 describes acompound represented by the following formula:

wherein X is a nitrogen atom or a CH group; R¹ is a hydrogen atom, alower alkyl group, an aryl group, or an aralkyl group; R² is a hydrogenatom or a lower alkyl group; the rings A and B are each independently asubstituted or unsubstituted benzene ring; and n is 1 or 2.(10) Japanese Patent Laid-Open Publication No. 2000-139834 describes acompound represented by the following formula:

wherein R¹ and R² are each independently a hydrogen atom or an C₁ to C₆alkyl group; R³ is a hydrogen atom, a substituted or unsubstituted C₁ toC₆ alkylcarbonyl group, a substituted or unsubstituted C₁ to C₆alkylsulfonyl group, a substituted or unsubstituted C₁ to C₆ alkylgroup, a substituted or unsubstituted arylmethyl group or analkoxycarbonyl group; the ring A is a homocyclic or heterocyclic ringwhich may include 1 through 3 independently selected substituents (anyadjacent two of which may be bound to one another to form a ring); thering B is a benzene ring which may include 1 through 5 substituents (anyadjacent two of which may be bound to one another to form a ring); andthe ring C is a benzene ring which may include 1 through 3 substituents(any adjacent two of which may be bound to one another to form a ring).(11) Japanese Patent Laid-Open Publication No. 2000-247957 describes acompound represented by the following formula:

wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom or thelike; R² and R²′ are each a hydrogen atom or the like; R³ is a hydrogenatom or the like; R⁴ is a hydrogen atom or the like; R⁵ is a hydrogenatom or the like; R⁶ is a hydrogen atom or the like; X is —C(O)N(R⁵)— orthe like; n is an integer from 0 to 4; and m is 1 or 2.(12) International Patent Publication No. WO0050401 describes a compoundrepresented by the following formula:

wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom or thelike; R² is a hydrogen atom or the like; R³ is a hydrogen atom or thelike; R⁴ is a hydrogen atom or the like; R⁵ is a hydrogen atom or thelike; R⁶ is a hydrogen atom or the like; X is —C(O)N(R⁵)— or the like; nis an integer from 0 to 4; and m is 1 or 2.(13) International Patent Publication No. WO0073279 describes a compoundrepresented by the following formula:

wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom or thelike; R³ is a hydrogen atom or the like; R⁴ and R⁴′ are each a hydrogenatom or the like; R⁵ is a lower alkyl group or the like; n is an integerfrom 0 to 2; and X is —C(O)N(R⁴″)— or the like.(14) International Patent Publication No. WO0073278 describes a compoundrepresented by the following formula:

wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom or thelike; R³ is a hydrogen atom or the like; R⁴ and R⁴′ are each a hydrogenatom or the like; R⁵ is a lower alkyl group or the like; R⁶ is ahydrogen atom or the like; n is an integer from 0 to 2; and X is—C(O)N(R⁴″)— or the like.

DISCLOSURE OF THE INVENTION

At present, no effective tachykinin antagonists (in particular, NK1receptor antagonists) have been discovered that can serve asprophylactic or therapeutic agents against the above-describedpathological conditions and at the same time meet requirements forpharmaceutical products, including safety, persistence of efficacy,pharmacokinetics, and pharmacological activities.

It is thus an objective of the present invention to provide a novelcompound that acts as an effective tachykinin receptor antagonist, inparticular as an NK1 receptor antagonist, and can thus serve as aprophylactic or a therapeutic agent against various pathologicalconditions that involve tachykinin receptors, including increasedurinary frequency, incontinence of urine, vomiting, inflammation,allergies, respiratory tract disorders, pains, and central nervoussystem disorders.

The present inventors have discovered that fused bicyclic pyridinederivatives that are represented by the following general formula (1),or salts thereof, can act as effective tachykinin receptor antagonists(in particular as NK1 receptor antagonists):(General Formula (1))

wherein the rings A and B are each a benzene ring which may include 1through 3 substituents (any adjacent two of which may be bound to oneanther to form a ring); the ring C is a nitrogen-containing ring havinga hydrogen atom substituted with a nitrogen atom; R¹ and R² are eachindependently a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆alkylsulfonyl group, a C₁ to C₆ alkylcarbonyl group, or a C₁ to C₆alkoxycarbonyl group, or R¹ and R² may be bound to one another to formthe ring D; m is 1 or 2; n is 2 or 3, and q is an integer from 1 to 4.As evidence, the present inventors have demonstrated in animalexperiments that these compounds can effectively relieve dysuria, atachykinin-mediated disorder. This discovery led the present inventorsto ultimately complete the present invention.

Accordingly, the present invention provides the followings:

(I) A fused bicyclic pyridine derivative represented by the followinggeneral formula (1), or a salt thereof:

(General Formula (1))

wherein the rings A and B are each a benzene ring which may have 1 to 3substituents (any adjacent two of which may be bound to one another toform a ring) that are each independently selected from the groupconsisting of a halogen atom, a substituted or unsubstituted C₁ to C₆alkyl group, and a substituted or unsubstituted C₁ to C₆ alkoxy group;

the ring C is a nitrogen-containing ring having a carbon atomsubstituted with a nitrogen atom;

R¹ and R² are each independently a hydrogen atom, a C₁ to C₆ alkylgroup, a C₁ to C₆ alkylsulfonyl group, a C₁ to C₆ alkylcarbonyl group,or a C₁ to C₆ alkoxycarbonyl group, or R¹ and R² are bound to oneanother to form the ring D, which is a 3- to 7-membered non-aromaticheterocyclic ring that may contain, aside from the nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom and may further contain 1 or 2 oxogroup-substituted carbon atoms;

m is 1 or 2; n is 2 or 3; and q is an integer from 1 to 4.

(II) A fused bicyclic pyridine derivative represented by the followinggeneral formula (1a), or a salt thereof:

(General Formula (1a))

wherein R³ and R⁴ are each independently a hydrogen atom, a fluorineatom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethylgroup, a methoxy group, or a trifluoromethoxy group;

the ring C is a nitrogen-containing ring having a carbon atomsubstituted with a nitrogen atom;

R¹ and R² are each independently a hydrogen atom, a C₁ to C₆ alkylgroup, a C₁ to C₆ alkylsulfonyl group, a C₁ to C₆ alkylcarbonyl group,or a C₁ to C₆ alkoxycarbonyl group, or R¹ and R² are bound to oneanother to form the ring D, which is a 3- to 7-membered non-aromaticheterocyclic ring that may contain, aside from the nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom and may further contain 1 or 2 oxogroup-substituted carbon atoms;

n is 2 or 3; and q is an integer from 1 to 4.

(III) The fused bicyclic pyridine derivative according to (II) above ora salt thereof, wherein in the general formula (1a), n is 3.

(IV) The fused bicyclic pyridine derivative according to (II) above or asalt thereof, wherein in the general formula (1a), n is 3, and q in thering C is 3.

(V) The fused bicyclic pyridine derivative according to (II) above or asalt thereof, wherein in the general formula (1a), n is 3, q in the ringC is 3, and the ring D is represented by the following formula:

wherein p is an integer from 1 to 4, and X is an oxygen atom, a nitrogenatom, or a sulfur atom.(VI) The fused bicyclic pyridine derivative according to (II) above or asalt thereof, wherein in the general formula (1a), n is 3, q in the ringC is 3, and the ring D is represented by the following formula:

wherein the ring D′ is a 3- to 7-membered cyclic amide that may contain,aside from the nitrogen atom, 1 to 3 heteroatoms selected from the groupconsisting of a nitrogen atom, a sulfur atom, and an oxygen atom.(VII) The fused bicyclic pyridine derivative according to (II) above ora salt thereof, wherein in the general formula (1a), n is 3, q in thering C is 3, and the ring D is represented by the following formula:

(VIII) The fused bicyclic pyridine derivative according to (II) above ora salt thereof, wherein in the general formula (1a), n is 3, q in thering C is 3, and R¹ and R² are each independently a hydrogen atom, amethyl group, an ethyl group, an acetyl group, or a methylsulfonylgroup.(IX) The compound according to (II) above, wherein the compoundrepresented by the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.(X) The compound according to (II) above, wherein the compoundrepresented by the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.(XI) The compound according to (II) above, wherein the compoundrepresented by the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.(XII) A tachykinin receptor antagonist containing as an activeingredient the fused bicyclic pyridine derivative according to any of(I) through (XI) above or a salt thereof.(XIII) An NK1 receptor antagonist containing as an active ingredient thefused bicyclic pyridine derivative according to any of (I) through (XI)above or a salt thereof.(XIV) A prophylactic or therapeutic agent for dysuria, includingdefective bladder functions such as increased urinary frequency andincontinence of urine, containing as an active ingredient the fusedbicyclic pyridine derivative according to any of (I) through (XI) aboveor a salt thereof.(XV) A prophylactic or therapeutic agent for disorders of digestivetract such as ulcerative colitis and Crohn's disease, containing as anactive ingredient the fused bicyclic pyridine derivative according toany of (I) through (XI) above or a salt thereof.(XVI) A prophylactic or therapeutic agent for vomiting induced byexposure to X-ray, chemotherapy, pregnancy, migraine, postoperativepains, decreased gastrointestinal motility, and side effects of drugs,containing as an active ingredient the fused bicyclic pyridinederivative according to any of (I) through (XI) above or a salt thereof.(XVII) A therapeutic agent for treating conditions, such as asthma,coughing, ache, migraine, tooth pain, and rheumatoid arthritis,containing as an active ingredient the fused bicyclic pyridinederivative according to any of (I) through (XI) above or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in detail.

Rings A and B

In the general formula (1), the rings A and B each represent a benzenering, which may include 1 to 3 substituents (any adjacent two of whichsubstituents may be bound to one another to form a ring). Thesubstituents on each of the rings A and B may be positioned at anypossible position with the number of the substituents on each ringvarying from about 1 to 3. Any adjacent two of these substituents may bebound to each other to form a ring. Examples of the substituents on therings A and B include halogen atoms, substituted or unsubstituted C₁ toC₆ alkyl groups, and substituted or unsubstituted C₁ to C₆ alkoxylgroups.

Examples of the halogen atoms include fluorine atom, chlorine atom,bromine atom and iodine atom.

Examples of the substituted or unsubstituted C₁ to C₆ alkyl groupsinclude C₁ to C₆ alkyl groups having 1 to 3 hydrogen atoms substitutedwith halogen atoms. Specific examples include methyl group, ethyl group,propyl group, isopropyl group, isobutyl group, sec-butyl group,tert-butyl group, fluoromethyl group, chloromethyl group, bromomethylgroup, iodomethyl group, 1-fluoroethyl group, 1-chloroethyl group,2-chloroethyl group, difluoromethyl group, trifluoromethyl group,trichloromethyl group, and 2,2,2-trifluoroethyl group.

Examples of the substituted or unsubstituted C₁ to C₆ alkoxyl groupsinclude C₁ to C₆ alkoxyl groups that have 1 to 3 hydrogen atomssubstituted with halogen atoms. Specific examples include methoxy group,ethoxy group, propoxy group, isopropoxy group, isobutoxy group,sec-butoxy group, tert-butoxy group, fluoromethoxy group, chloromethoxygroup, bromomethoxy group, iodomethoxy group, 1-fluoroethoxy group,1-chloroethoxy group, 2-fluoroethoxy group, difluoromethoxy group,trifluoromethoxy group, trichloromethoxy group, and2,2,2-trifluoroethoxy group.

Examples of the rings with two adjacent substituents being bound to eachother to form a ring include the followings:

Ring A

Preferred examples of the ring A are those represented by the followingformulae:

(wherein R⁵, R⁶, and R⁷ are each independently a fluorine atom, achlorine atom, a methyl group, an ethyl group, a trifluoromethyl group,a methoxy group, or a trifluoromethoxy group.)

Particularly preferred examples of the ring A are those represented bythe following formulae:

Ring B

Preferred examples of the ring B include those represented by thefollowing formula:

Ring C

q is an integer from 1 to 4, and preferably, 3. Thus, examples of thering C in the general formula (1) include azetidine, pyrrolidine,piperidine, and homopiperidine rings.

Preferred examples of the ring C are pyrrolidine and piperidine rings.

Particularly preferred examples of the ring C include piperidine rings.

Positions of N-Atom Substitution on Ring C

The ring C may be substituted with nitrogen atom at any possibleposition. When the ring C is a piperidine ring, the ring is preferablysubstituted at a position shown by the following formula:

R¹ and R²

R¹ and R² may be bound to each other to form the ring D or are eachindependently a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆alkylsulfonyl group, a C₁ to C₆ alkylcarbonyl group, or a C₁ to C₆alkoxycarbonyl group. Examples of the C₁ to C₆ alkyl groups includemethyl group, ethyl group, propyl group, isopropyl group, isobutylgroup, sec-butyl group, and tert-butyl group.

Examples of the C₁ to C₆ alkylsulfonyl groups include methylsulfonylgroup, ethylsulfonyl group, and propylsulfonyl group.

Examples of the C₁ to C₆ alkylcarbonyl groups include methylcarbonylgroup, ethylcarbonyl group, and propylcarbonyl group.

Examples of the C₁ to C₆ alkoxycarbonyl groups include methoxycarbonylgroup, ethoxycarbonyl group, propoxycarbonyl group, andtert-butoxycarbonyl group.

Ring D

The ring D represents a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected form the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo group-substitutedcarbon atoms. Preferred examples are nonaromatic heterocyclic ringsrepresented by the following formulae:

Particularly preferred are nonaromatic heterocyclic rings represented bythe following formula:

m

m is 1 or 2, and preferably, 1.

n

n is 2 or 3, and preferably, 3.

Preferred examples of the compounds of the present invention include5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(piperidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;9-(4-aminopiperidine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(methylamino)pyrrolidine-1-yl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-8-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine;4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine;4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine;9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine;and9-[4-(methylsulfonylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.

Salts

Examples of pharmaceutically acceptable salts of the compounds of thepresent invention include those formed with inorganic acids, such ashydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, andthose formed with organic acids, such as acetic acid, maleic acid,fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylicacid, stearic acid, and palmitic acid.

Aside from racemic mixtures, the compounds of the present invention orsalts thereof may be provided in the form of optically active forms,stereoisomers, or atrop isomers.

The compounds of the present invention or salts thereof may also existin the form of hydrates or solvates. The present invention encompassesany hydrates or solvates formed by the fused bicyclic pyridinederivatives of the general formula (1a), including the preferredcompounds specifically mentioned above, or salts thereof. Examples ofthe solvents that can form solvates include methanol, ethanol,isopropanol, acetone, ethyl acetate, methylene chloride, anddiisopropylether.

Various synthetic techniques may be used to produce the compounds of thepresent invention. One commonly-used production process of the compoundsof the present invention or salts thereof is as follows:

(Step 1)

In this step, a compound (a) (wherein R⁸ represents a hydroxyl group, ahalogen atom, a 1-imidazolyl group, a 4-nitrophenoxy group, animidoyloxy succinate group, a C₁ to C₆ alkoxyl group, a benzyloxy group,or the like) and a compound (b) (wherein the ring B is as describedabove) are allowed to undergo condensation to generate a compound (c)(wherein the ring B is as described above). When R⁸ is a hydroxyl group,a suitable condensation agent for use in the condensation reaction inthis step may be dicyclohexylcarbodiimide (DCC),3-ethyl-1-(3-dimethylaminopropyl)carbodimide hydrochloride (EDCI), ordimethylimidazolinium chloride (DMC). These condensation agents may beadded in the form of a solid product or a solution in a proper solvent.A base may be used in the condensation reaction, including alkalicarbonates, such as sodium hydrogen carbonate, or potassium carbonate,and tertially amines, such as triethylamine, diisopropylethylamine,N-methylmorpholine, diazabicyclo[5.4.0]-7-undecene, pyridine,4-dimethylaminopyridine, or 1,8-bis(dimethylamino)naphthalene. Thesolvent for use in the condensation reaction may be any inert solventthat is not involved in the reaction, including N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran,dioxane, ethyl ether, dimethoxyethane, ethylacetate, anddichloromethane. The condensation reaction may be carried out at −20° C.to 80° C. When the compound (a) for use in the condensation reaction inthis step is any of a halide of a carboxylic acid, an imidazolide of acarboxylic acid, or an active ester of a carboxylic acid, in which R⁸ isa halogen atom, a 1-imidazolyl group, a 4-nitrophenoxy group or animidoyloxy succinate group, the reaction can be carried out by allowingthe reactants to react in the presence or absence of an organic base,such as triethylamine, diisopropylethylamine, pyridine or4-dimethylaminopyridine, or an inorganic base, such as sodium hydrogencarbonate or potassium carbonate, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane,ethylacetate, toluene or dichloromethane, at −20° C. to 80° C. for 30min. to 48 hours. When R⁸ is a C₁ to C₆ an ester residue such as analkoxyl group and a benzyloxy group in the condensation reaction in thisstep, the reaction can be carried out by allowing the reactants to reactin the presence or absence of trimethylaluminium ortetraisopropoxytitanium or in the presence or absence of an acidic or abasic catalyst, such as p-toluenesulfonic acid, sodium methoxide,potassium t-butoxide, or sodium hydride, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene,pyridine, quinoline, or dichloromethane, at 15° C. to 150° C. for 30min. to 48 hours.

(Step 2)

In this step, the compound (c) (wherein the ring B is as describedabove) is cyclized to generate a compound (d) (wherein the ring B is asdescribed above). The step may be carried out by allowing thecyclization to take place in the presence or absence of an organic base,such as sodium-tert-butoxide or potassium-tert-butoxide, or an inorganicbase, such as sodium hydride, potassium carbonate, sodium carbonate,cesium carbonate or sodium acetate, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene,pyridine, quinoline, or dichloromethane, at 0° C. to 150° C. for 30 min.to 48 hours.

(Step 3)

In this step, the compound (d) (wherein the ring B is as describedabove) and a compound (e) (wherein the ring A is as described above, Yis a halogen atom, OSO₂R⁹ (wherein R⁹ is a halogen-substituted orunsubstituted C₁ to C₆ alkyl group) or B(R¹⁰)₂ (R¹⁰ substituents areeach independently a hydroxyl group, a C₁ to C₆ alkyl group, or a C₁ toC₆ alkoxyl group, or R¹⁰ substituents may be bound to each other to forma ring)) are allowed to undergo cross-coupling in the presence of atransitional metal catalyst such as a palladium or nickel complex togenerate a compound (f) (wherein the rings A and B are as describedabove). Preferably, the process is carried out by using an inert solventthat is not involved in the process, including N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran,dioxane, dichloromethane, toluene, ethanol or water. These solvents maybe used individually or they may be mixed in any proportion. Examples ofthe palladium complexes for use in the process include palladiumchloride, palladium acetate, acetylacetonato palladium, andtetrakis(triphenylphosphine)palladium. Examples of the nickel complexesfor use in the process include bis(acetylacetonato)nickel,bis(1,5-cyclooctadiene)nickel, and tetrakis(triphenylphosphine)nickel.Each of these palladium or nickel complexes is used in an amount of0.001 to 1 equivalent, preferably in an amount of 0.01 to 0.1equivalent, with respect to the compound (d). When it is desired to usea ligand for the palladium or nickel complex in the process, such aligand may be triphenylphosphine, tri-o-tolylphosphine,tri-2-furylphosphine, 1,2-bis(diphenylphosphino)ethane,1,1′-bis(diphenylphosphino)ferrocene, or2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Each of these ligands isused in an amount of 0.2 to 5 equivalents, preferably in an amount of0.3 to 3 equivalents, with respect to the palladium or nickel complex.Preferably, the process is carried out in the presence of a proper base.Among such bases are organic bases, including triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,lutidine, and collidine, and inorganic bases, including sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate,cesium carbonate, and tripotassium phosphate. Each of these bases isused in an amount of 1 to 20 equivalents, preferably in an amount of 2to 10 equivalents, with respect to the compound (d). The cross-couplingreaction in this step is carried out by allowing the reactants toundergo the reaction at 15 to 150° C., preferably at 50 to 120° C., for30 min. to 24 hours.

(Step 4)

In this step, the compound (f) (wherein the rings A and B are asdescribed above) is oxidized at the nitrogen on its pyridine ring togenerate a compound (g) (wherein the rings A and B are as describedabove). The step may be carried out by using a peroxide (such asm-chloroperbenzoic acid, hydrogen peroxide, and peracetic acid) in anamount of 1 to 10 equivalents, preferably in an amount of 1 to 2equivalents, with respect to the compound (f) and by allowingoxidization to proceed at −20° C. to 80° C., preferably at 0 to 30° C.,for 30 min. to 72 hours. The solvent for use in this step may bedichloromethane, toluene, ethyl acetate, dimethoxyethane, ethyl ether,dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, andN,N-dimethylacetamide.

(Step 5)

In this step, Z (wherein Z represents a halogen atom) is introduced intothe compound (g) (wherein the rings A and B are as described above) withthe help of the N-oxide to generate a compound (h). When Z is a chlorineatom, the step may be carried out by using such a chlorinating agent asphosphorus oxychloride, pivaloyl chloride, and oxalyl chloride in anamount of 1 to 20 equivalents, preferably in an amount of 2 to 10equivalents, with respect to the compound (g) and by allowing thereaction to proceed at 15 to 120° C., preferably at 80 to 120° C., for30 min. to 24 hours. When it is desired to use a base in the process,such a base may be triethylamine, tributylamine, diisopropylethylamine,N-methylmorpholine, pyridine, lutidine, or collidine. When it is desiredto use a solvent, it may be any inert solvent that is not involved inthe reaction, including dichloromethane, xylene, toluene, dioxane, andtetrahydrofuran.

(Step 6)

In this step, the compound (h) (wherein Z, and the rings A and B are asdescribed above) is reacted with a compound (i) to generate a compound(j) (R¹, R², and the rings A and B are as described above). The reactioncan be carried out by using the compound (i) in an amount of 1 to 20equivalents of the compound (h) and allowing the reactants to react inthe presence or absence of a base at 80 to 200° C., preferably at 120 to150° C., for 30 min. to 24 hours. A base may preferably be used,including organic bases, such as trimethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine, lutidine,collidine, and N,N-dimethylaniline, and inorganic bases, such as sodiumhydrogen carbonate, sodium carbonate, potassium carbonate, calciumcarbonate, cesium carbonate, and tripotassium phosphate. When it isdesired to use a solvent, such a solvent may be any inert solvent thatis not involved in the reaction, including N,N-dimethylformamide,N,N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran,dioxane, xylene, toluene, ethanol and water.

The compounds (1) of the present invention can be isolated/purified byordinary means (for example, extraction, recrystallization,distillation, and chromatography). When the resulting compounds tend toform salts, such salts can be produced by ordinary techniques orequivalent techniques (for example, neutralization).

The compounds (1) of the present invention or salts thereof act astachykinin receptor antagonists, in particular NK1 receptor antagonists,and are thus useful as:

prophylactic or therapeutic agents for dysuria, including defectivebladder functions such as increased urinary frequency and incontinenceof urine;

prophylactic or therapeutic agents for disorders of digestive tract suchas ulcerative colitis and Crohn's disease;

prophylactic or therapeutic agents for vomiting induced by exposure toX-ray, chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs;

prophylactic or therapeutic agents for vomiting induced by exposure toX-ray, chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs; and

therapeutic agents for asthma, coughing, ache, migraine, tooth pain,rheumatoid arthritis and other conditions.

The compounds (1) of the present invention or salts thereof may be usedindividually, or they may be formed into pharmaceutical compositionsalong with one or more pharmaceutically acceptable adjuvants.Specifically, the compounds of the present invention may be mixed withpharmaceutically acceptable carriers, excipients (such as starch,lactose, calcium phosphate, and calcium carbonate), lubricants (such asmagnesium stearate, calcium stearate, talc, and stearic acid), binders(such as starch, cellulose crystals, carboxymethylcellulose, gum Arabic,polyvinylpyrrolidone, and alginic acid), disintegrating agents (such astalc, and carboxymethylcellulose calcium), and diluents (such asphysiological saline, and aqueous solutions of glucose, mannitol andlactose). Using ordinary techniques, the compounds of the presentinvention may be prepared as tablets, capsules, granules, powders, finegranules, ampules, or injections for oral or parenteral administration.While the dosage of the compounds (1) of the present invention or saltsthereof may vary depending on the type of salt, route of administration,and age and conditions of patients, a typical dose for humans and othermammals, for example, is in the range of 0.0001 to 300 mg/kg/day asmeasured by the amount of the compounds (1) of the present invention orsalts thereof. The compounds (1) or salts thereof may be administered ina single dose or several doses each day.

EXAMPLES

The present invention will now be described in detail with reference toExamples, Reference Examples, and Test Examples, as will an exemplaryproduction process of a starting material of the compounds (1) of thepresent invention, which is also a novel compound. It should beappreciated that the compounds of the present invention are not limitedto those described in the following examples and may be modified withoutdeparting from the scope and the spirit of the invention.

Example 1

A mixture of5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(40.0 mg) and 4-(pyrrolidine-1-yl)piperidine (30.0 mg) was stirred at150° C. for 3 hours. To the remaining product, water was added and themixture was extracted with ethyl acetate. The extract was then washedwith a saturated aqueous solution of sodium hydrogen carbonate and wasdried on anhydrous sodium sulfate. The solvent was removed and theresulting residue was purified on a silica gel column chromatography(ethyl acetate:methanol=3:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(25.0 mg, 51%).

MS (FAB⁺)m/z: 633 (M+H⁺).

HRMS (FAB⁺): Calcd for C₃₃H₃₅F₆N₄O₂: 633.2664; found: 633.2638.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.50-1.63 (2H, m), 1.73-1.88 (5H, m),1.93-2.03 (2H, m), 2.13-2.33 (2H, m), 2.56-2.67 (4H, m), 2.90-3.03 (2H,m), 3.27-3.34 (1H, m), 3.86 (1H, t, J=16.7 Hz), 4.09 (1H, d, J=15.6 Hz),4.23-4.33 (2H, m), 4.36-4.45 (1H, m), 4.45-4.53 (1H, m), 5.42 (1H, d,J=15.6 Hz), 6.37 (1H, s), 7.22-7.38 (5H, m), 7.70 (2H, s), 7.80 (1H, s).

Example 2

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(40.0 mg) was reacted with 4-(piperidine-1-yl)piperidine (32.7 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(piperidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(24.0 mg, 48%).

MS (EI) m/z: 646 (M⁺).

HRMS (EI): Calcd for C₃₄H₃₆F₆N₄O₂: 646.2742; found: 646.2731.

Example 3

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(67.4 mg, 56%).

MS (EI) m/z: 666 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₃ClF₆N₄O₂: 666.2196; found: 666.2201.

Example 4

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (68.5 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(54.7 mg, 45%).

MS (EI) m/z: 650 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₃F₇N₄O₂: 650.2492; found: 650.2451.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.50-1.63 (2H, m), 1.63-1.85 (5H, m),1.93-2.02 (2H, m), 2.13-2.32 (2H, m), 2.56-2.65 (4H, m), 2.91-3.04 (2H,m), 3.26-3.34 (1H, m), 3.83 (1H, t, J=13.7 Hz), 4.10 (1H, d, J=15.1 Hz),4.23-4.32 (2H, m), 4.36-4.43 (1H, m), 4.46-4.53 (1H, m), 5.40 (1H, d,J=15.1 Hz), 6.33 (1H, s), 6.96-7.03 (2H, m), 7.19-7.25 (2H, m), 7.67(2H, s), 7.81 (1H, s).

Example 5

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(63.4 mg, 52%).

MS (EI) m/z: 650 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₃F₇N₄O₂: 650.2492; found: 650.2451.

Example 6

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(57.7 mg, 48%).

MS (EI) m/z: 666 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₃ClF₆N₄O₂: 666.2196; found: 666.2206.

Example 7

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(58.2 mg, 48%).

MS (EI) m/z: 646 (M⁺).

HRMS (EI): Calcd for C₃₄H₃₆F₆N₄O₂: 646.2742; found: 646.2704.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.50-2.01 (10H, m), 2.04-2.20 (1H, m),2.20-2.36 (3H, m), 2.54-2.67 (4H, m), 2.88-3.02 (2H, m), 3.11-3.23 (1H,m), 3.63-3.83 (1H, m), 3.90-3.99 (1H, m), 4.20-4.51 (4H, m), 5.32-5.43(1H, m), 6.26 (1H, s), 6.76-7.33 (4H, m), 7.53 (2H, s), 7.76 (1H, s).

Example 8

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(47.6 mg) was reacted with 4-(dimethylamino)piperidine (28.8 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(23.1 mg, 41%).

MS (EI) m/z: 620 (M⁺).

HRMS (EI): Calcd for C₃₂H₃₄F₆N₄O₂: 620.2586; found: 620.2560.

Example 9

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(47.6 mg) was reacted with 4-(morpholine-4-yl)piperidine (38.3 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(24.2 mg, 41%).

MS (EI) m/z: 662 (M⁺).

HRMS (EI): Calcd for C₃₄H₃₆F₆N₄O₃: 662.2692; found: 662.2655.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.20-1.98 (5H, m), 2.03-2.20 (1H, m), 2.31(2H, s), 2.38-2.47 (1H, m), 2.52-2.60 (4H, m), 2.83-2.95 (2H, m),3.13-3.22 (1H, m), 3.69-3.77 (6H, m), 3.90-3.97 (1H, m), 4.27-4.50 (4H,m), 5.32-5.43 (1H, m), 6.26 (1H, s), 6.76-7.33 (4H, m), 7.53 (2H, s),7.76 (1H, s).

Example 10

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(47.6 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (38.0 mg)to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(23.1 mg, 39%).

MS (EI) m/z: 660 (M⁺).

HRMS (EI): Calcd for C₃₄H₃₄F₆N₄O₃: 660.2535; found: 660.2499.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.64-1.80 (4H, m), 1.80-1.93 (2H, m),1.97-2.06 (2H, m), 2.06-2.20 (1H, m), 2.32 (2H, s), 2.41 (2H, t, J=7.8Hz), 2.88-3.03 (2H, m), 3.14-3.23 (1H, m), 3.33 (2H, t, J=7.8 Hz),3.64-3.84 (1H, m), 3.91-3.98 (1H, m), 4.19-4.68 (5H, m), 5.32-5.43 (1H,m), 6.27 (1H, s), 6.76-7.33 (4H, m), 7.53 (2H, s), 7.76 (1H, s).

Example 11

A mixture of5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(40.0 mg) and 4-(t-butoxycarbonylamino)piperidine (38.9 mg) was stirredat 140° C. for 5 hours. To the remaining product, water was added andthe mixture was extracted with ethyl acetate, followed by drying onanhydrous sodium sulfate. The solvent was then removed to obtain aresidue. To this residue, a 3 mol/L ethyl acetate solution of hydrogenchloride (1 mL) was added and the mixture was stirred at roomtemperature for 1 hour. The solvent was again removed to obtain aresidue. To this residue, ethyl acetate was added and the mixture waswashed with a saturated aqueous solution of sodium hydrogen carbonate,followed by drying on anhydrous sodium sulfate. The solvent was thenremoved and the resulting residue was purified on a silica gel columnchromatography (ethyl acetate:methanol=3:1) to obtain9-(4-aminopiperidine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(35.0 mg, 78%).

MS (EI) m/z: 578 (M⁺).

HRMS (EI): Calcd for C₂₉H₂₈F₆N₄O₂: 578.2116; found: 578.2147.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.36-1.48 (2H, m), 1.59-1.88 (5H, m),1.88-1.98 (2H, m), 2.12-2.25 (1H, m), 2.92-3.05 (2H, m), 3.27-3.36 (1H,m), 3.89 (1H, t, J=13.7 Hz), 4.09 (1H, d, J=15.1 Hz), 4.23-4.39 (2H, m),4.45-4.52 (1H, m), 5.42 (1H, d, J=15.1 Hz), 6.37 (1H, s), 7.23-7.38 (5H,m), 7.70 (2H, s), 7.80 (1H, s).

Example 12

In a similar manner to Example 11,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(40.0 mg) was reacted with3-(N-(t-butoxycarbonyl)-N-methylamino)pyrrolidine (38.9 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(methylamino)pyrrolidine-1-yl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(22.5 mg, 50%).

MS (EI) m/z: 578 (M⁺).

HRMS (EI): Calcd for C₂₉H₂₈F₆N₄O₂: 578.2116; found: 578.2080.

Example 13

A mixture of5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(47.6 mg), 4-(t-butoxycarbonylamino)piperidine (45.1 mg), and1,4-dioxane (1 mL) was stirred at 150° C. for 3 hours. The solvent wasthen removed to obtain a residue. To this residue, a 3 mol/L ethylacetate solution of hydrogen chloride (1 mL) was added and the mixturewas stirred at room temperature for 1 hour. The solvent was removed andthe resulting residue was dissolved in tetrahydrofuran (1 ml). While thesolution was chilled on an ice bath, triethylamine (60 μl) andacetylchloride (30 μl) were added, and the mixture was stirred at roomtemperature for 30 min. This was followed by the addition of ethylacetate, and the mixture was washed with water and was then dried onanhydrous sodium sulfate. Subsequently, the solvent was removed and theresulting residue was purified on a silica gel column chromatography(ethyl acetate) to obtain9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(19.2 mg, 34%).

MS (EI) m/z: 634 (M⁺).

HRMS (EI): Calcd for C₃₂H₃₂F₆N₄O₃: 634.2379; found: 634.2392.

¹H-NMR (400 Mz, CDCl₃) ppm: 1.34-1.48 (2H, m), 1.80-1.95 (2H, m),1.95-2.20 (6H, m), 2.31 (2H, s), 2.95-3.08 (2H, m), 3.12-3.23 (1H, m),3.64-3.83 (1H, m), 3.90-3.98 (1H, m), 3.98-4.10 (1H, m), 4.14-4.26 (1H,m), 4.26-4.51 (3H, m), 5.31-5.43 (2H, m), 6.26 (1H, s), 6.76-7.33 (4H,m), 7.52 (2H, s), 7.76 (1H, s).

Example 14

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(53.3 mg) was reacted with 4-(dimethylamino)piperidine (15.4 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(22.6 mg, 36%).

MS (EI) m/z: 624 (M⁺).

HRMS (EI): Calcd for C₃₁H₃₁F₇N₄O₂: 624.2335; found: 624.2291.

Example 15

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(53.3 mg) was reacted with 4-(morpholine-4-yl)piperidine (20.4 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(26.2 mg, 39%).

MS (EI) m/z: 666 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₃F₇N₄O₃: 666.2441; found: 666.2433.

Example 16

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(53.3 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (20.2 mg)to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(26.1 mg, 39%).

MS (EI) m/z: 664 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₁F₇N₄O₃: 664.2284; found: 664.2325.

Example 17

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(82.0 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (69.5 mg) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(38.4 mg, 39%).

MS (EI) m/z: 662 (M⁺).

HRMS (EI): Calcd for C₃₄H₃₆F₆N₄O₃: 662.2692; found: 662.2711.

Example 18

In a similar manner to Example 1,4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(51.5 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (46.3 mg) toobtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-8-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(8.6 mg, 14%).

MS (EI) m/z: 632 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₄F₆N₄O₂: 632.2586; found: 632.2571.

Example 19

In a similar manner to Example 1,4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(51.5 mg) was reacted with 4-(morpholine-4-yl)piperidine (51.1 mg) toobtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(8.3 mg, 13%).

MS (EI) m/z: 648 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₄F₆N₄O₃: 648.2535; found: 648.2526.

Example 20

In a similar manner to Example 1,4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(51.5 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (50.5 mg)to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(5.2 mg, 8%).

MS (EI) m/z: 646 (M⁺).

HRMS (EI): Calcd for C₃₃H₃₂F₆N₄O₃: 646.2379; found: 646.2352.

Example 21

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(53.3 mg) was reacted with 4-(t-butoxycarbonylamino)piperidine (24.0 mg)to obtain9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(13.7 mg, 21%).

MS (EI) m/z: 638 (M⁺).

HRMS (EI): Calcd for C₃₁H₂₉F₇N₄O₃: 638.2128; found: 638.2155.

Example 22

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(53.3 mg) was reacted with 4-(t-butoxycarbonylamino)piperidine (24.0 mg)to obtain9-[4-(methylsulfonylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(20.4 mg, 30%).

MS (EI) m/z: 674 (M⁺).

HRMS (EI): Calcd for C₃₀H₂₉F₇N₄O₄S: 674.1798; found: 674.1806.

Reference Example 1

To a tetrahydrofuran solution of lithium diisopropylamide (which wasprepared by diluting diisopropylamine (14.6 mL) with tetrahydrofuran(200 mL), followed by addition of n-butyllithium (69.5 mL, 1.5 mol/Lhexane solution) at −20° C. and then a 30-minute stirring period at −20°C.), a tetrahydrofuran solution (100 mL) of 2-chloro-3-iodopyridine(23.8 g) was added at −78° C. and the mixture was stirred for 5 hours.Carbon dioxide was then bubbled through the reaction mixture for 1 hourand water was added. The temperature of the mixture was then allowed torise to room temperature. Following the addition of 2 mol/L hydrochloricacid (200 mL) to adjust the pH of the mixture to a value of 1, themixture was extracted with a 1:1 mixture of tetrahydrofuran and ethylacetate and was dried on anhydrous sodium sulfate. The solvent was thenremoved to obtain a residue. To this residue, ethyl acetate was addedand the resultant crystals were collected by filtration. As a result,2-chloro-4-iodonicotinic acid was obtained (22.7 g, 81%).

MS (EI) m/z: 283 (M⁺).

HRMS (EI): Calcd for C₆H₃ClINO₂: 282.8897; found: 282.8896.

Reference Example 2

To thionyl chloride (20 mL), 2-chloro-4-iodonicotinic acid (8.40 g) wereadded along with N,N-dimethylformamide (3 droplets) and the mixture wasstirred at 100° C. for 3 hours. The reaction mixture was then distilledunder reduced pressure to obtain a yellow residue.3-(3,5-bis(trifluoromethyl)benzylamino)propanol (10.7 g) andtriethylamine (20.6 mL) were dissolved in tetrahydrofuran (150 mL).While the mixture was chilled on an ice bath, a tetrahydrofuran solutionof the yellow residue (50 mL) was added. After stirred for 1 hour, themixture was further stirred for additional two hours at roomtemperature. Subsequently, water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was then driedon anhydrous sodium sulfate. Following the removal of the solvent, theremaining residue was purified on a silica gel column chromatography(ethyl acetate:n-hexane=3:1) to obtainN-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide(15.4 g, 92%).

MS (EI) m/z: 566 (M⁺).

HRMS (EI): Calcd for C₁₈H₁₄ClF₆N₂O₂: 565.9693; found: 565.9731.

Reference Example 3

N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide(6.86 g) was dissolved in tetrahydrofuran (60 mL). While the mixture waschilled on an ice bath, sodium hydride (581 mg, 60% oil suspension) wasadded and the mixture was stirred for 30 min. Subsequently, thetemperature of the mixture was allowed to rise to room temperature andthe mixture was stirred for another hour. While the mixture was chilledon an ice bath, water was added and the resulting mixture was extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride and was then dried on anhydrous sodiumsulfate. The solvent was removed and the resulting residue was purifiedon a silica gel column chromatography (ethyl acetate:n-hexane=2:1) toobtain5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(2.69 g, 42%).

MS (EI) m/z: 530 (M⁺).

HRMS (EI): Calcd for C₁₈H₁₃F₆IN₂O₂: 529.9926; found: 529.9907.

Reference Example 4

Phenylboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (132mg), toluene (10 mL), 1,4-dioxane (5 mL), and a 2 mol/L aqueous solutionof sodium carbonate (10 mL) were added to5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(1.00 g). While heated, the mixture was stirred for 7 hours under astream of argon gas. The mixture was then diluted with ethyl acetate,was washed with a 2 mol/L aqueous solution of sodium carbonate, and wasdried on anhydrous sodium sulfate. The solvent was removed and theresulting residue was recrystallized from isopropanol to obtain5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(729 mg, 80%).

MS (EI) m/z: 480 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₈F₆N₂O₂: 480.1272; found: 480.1286.

Reference Example 5

In a similar manner to Reference Example 4,5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(300 mg) was reacted with 4-chlorophenylboronic acid (160 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(292 mg, 100%). M

S (EI) m/z: 514 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₇ClF₆N₂O₂: 514.0883; found: 514.0878.

Reference Example 6

In a similar manner to Reference Example 4,5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(300 mg) was reacted with 4-fluorophenylboronic acid (143 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(284 mg, 100%).

MS (EI) m/z: 498 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₇F₇N₂O₂: 498.1178; found: 498.1168.

Reference Example 7

In a similar manner to Reference Example 4,5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(300 mg) was reacted with 2-fluorophenylboronic acid (143 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(218 mg, 77%).

MS (EI) m/z: 498 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₇F₇N₂O₂: 498.1178; found: 498.1168.

Reference Example 8

In a similar manner to Reference Example 4,5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(300 mg) was reacted with 2-chlorophenylboronic acid (133 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(254 mg, 87%).

MS (FAB⁺) m/z: 515 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₈ClF₆N₂O₂: 515.0961; found: 515.0932.

Reference Example 9

In a similar manner to Reference Example 4,5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(300 mg) was reacted with 2-methylphenylboronic acid (116 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(278 mg, 99%).

MS (EI) m/z: 494 (M⁺).

HRMS (EI): Calcd for C₂₅H₂₀F₆N₂O₂: 494.1429; found: 494.1441.

Reference Example 10

5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(729 mg) was dissolved in methylene chloride (10 mL) and3-chloroperbenzoic acid (524 mg) was added to the solution. Theresulting mixture was then stirred at room temperature for 24 hours. Thereaction mixture was purified on a silica gel column chromatography(ethyl acetate:methanol=5:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (411 mg, 54%).

MS (FAB⁺) m/z: 497 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₉F₆N₂O₃: 497.1300; found: 497.1291.

Reference Example 11

In a similar manner to Reference Example 10,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(290 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (112 mg, 37%).

MS (FAB⁺) m/z: 531 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₈ClF₆N₂O₃: 531.0910; found: 531.0892.

Reference Example 12

In a similar manner to Reference Example 10,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(272 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (119 mg, 42%).

MS (FAB⁺) m/z: 515 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₈F₇N₂O₃: 515.1206; found: 515.1230.

Reference Example 13

In a similar manner to Reference Example 10,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(238 mg) was use to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (178 mg, 72%).

MS (FAB⁺) m/z: 515 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₈F₇N₂O₃: 515.1206; found: 515.1189.

Reference Example 14

In a similar manner to Reference Example 10,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(250 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (207 mg, 80%).

MS (FAB⁺) m/z: 531 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₈ClF₆N₂O₃: 531.0910; found: 531.0877.

Reference Example 15

In a similar manner to Reference Example 10,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(270 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (231 mg, 83%).

MS (FAB⁺) m/z: 511 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₅H₂₁F₆N₂O₃: 511.1456; found: 511.1469.

Reference Example 16

5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (400 mg) was added to phosphorus oxychloride (1.5 mL), and themixture was refluxed for 1 hour while heated. The solvent was removed toobtain a residue. To this residue, ethyl acetate was added and theresulting crystals were collected. As a result,5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocinewas obtained (440 mg, 99%).

MS (EI) m/z: 514 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₇ClF₆N₂O₂: 514.0883; found: 514.0865.

Reference Example 17

In a similar manner to Reference Example 16,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (107 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(111 mg, 100%).

MS (EI) m/z: 548 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₆Cl₂F₆N₂O₂: 548.0493; found: 548.0508.

Reference Example 18

In a similar manner to Reference Example 16,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (114 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(118 mg, 100%).

MS (EI) m/z: 532 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₆ClF₇N₂O₂: 532.0798; found: 532.0801.

Reference Example 19

In a similar manner to Reference Example 16,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (170 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(176 mg, 100%).

MS (EI) m/z: 532 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₆ClF₇N₂O₂: 532.0789; found: 532.0824.

Reference Example 20

In a similar manner to Reference Example 16,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-dioxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (196 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(203 mg, 100%).

MS (FAB⁺) m/z: 549 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₇Cl₂F₆N₂O₂: 549.0571; found: 549.0605.

Reference Example 21

In a similar manner to Reference Example 16,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine10-oxide (220 mg) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(228 mg, 100%).

MS (EI) m/z: 528 (M⁺).

HRMS (EI): Calcd for C₂₅H₁₉ClF₆N₂O₂: 528.1039; found: 528.1063.

Reference Example 22

In a similar manner to Reference Example 4, 2-chloro-4-iodonicotinicacid (Compound of Reference Example 1; 5.67 g) was reacted with2-methylphenylboronic acid (3.00 g) to obtain2-chloro-4-(2-methylphenyl)nicotinic acid (4.44 g, 90%).

MS (EI) m/z: 247 (M⁺).

HRMS (EI): Calcd for C₁₃H₁₀ClNO₂: 247.0400; found: 247.0410.

Reference Example 23

2-chloro-4-(2-methylphenyl)nicotinic acid (Compound of Reference Example22; 670 mg) and N,N-dimethylformamide (2 droplets) were added to thionylchloride (2.0 mL). While heated, the mixture was refluxed for 1 hour.The reaction mixture was distilled under reduced pressure to obtain acolorless residue.

3-(3,5-bis(trifluoromethyl)benzylamino)propanol (Prepared according to amethod described in Japanese Patent Laid-Open Publication No. Hei9-263585; 818 mg) and triethylamine (1.9 mL) were dissolved intetrahydrofuran (8 mL). While this solution was chilled on an ice bath,the yellow residue in tetrahydrofuran (2 mL) was added. After stirredfor 1 hour, the mixture was further stirred for an additional 1 hour atroom temperature. Subsequently, the mixture was diluted with ethylacetate. The diluted mixture was successively washed with water, asaturated aqueous solution of sodium hydrogen carbonate, a 20% aqueouscitric acid, and a saturated aqueous solution of sodium chloride, andwas then dried on anhydrous sodium sulfate. The solvent was removed andthe resulting residue was dissolved in tetrahydrofuran (8 mL). Whilethis solution was chilled on an ice bath, potassium-t-butoxide (365 mg)was added. After stirred for 1 hour, the mixture was further stirred foran additional 1 hour at room temperature. Following dilution with ethylacetate, the mixture was successively washed with water and a saturatedaqueous solution of sodium chloride and was then dried on anhydroussodium sulfate. The solvent was removed and the resulting residue waspurified on a silica gel column chromatography (ethylacetate:n-hexane=2:1) to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(590 mg, 45%).

MS (EI) m/z: 480 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₈F₆N₂O₂: 480.1272; found: 480.1293.

Reference Example 24

In a similar manner to Reference Example 10,4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine(Compound of Reference Example 23; 530 mg) was used to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine10-oxide (333 mg, 61%).

MS (FAB⁺) m/z: 497 (M+H⁺).

HRMS (FAB⁺): Calcd for C₂₄H₁₉F₆N₂O₃: 497.1300; found: 497.1311.

Reference Example 25

In a similar manner to Reference Example 16,4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine10-oxide (Compound of Reference Example 24; 310 mg) was used to obtain4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine10-oxide (320 mg, 100%).

MS (EI) m/z: 514 (M⁺).

HRMS (EI): Calcd for C₂₄H₁₇ClF₆N₂O₂: 514.0883; found: 514.0840.

Evidence of the effectiveness of the compounds of the present inventionis provided below with reference to Test Examples.

Test Examples

(1) Test for NK1 Receptor Antagonist

The method used was according to the method proposed by S. Dion et al.(Dion et al., Life Sciences 41 (1987): 2269), to which minormodifications were made.

Guinea pigs were stunned by a blow on the head and were exsanguinatedfrom the carotid artery and ileum was isolated. The ileum was mounted inan organ bath containing Tyrode's solution which was maintained at 32°C. and gased with 95% O₂ and 5% CO₂. The ileum was subjected to aresting tension of 1-gram and allowed to equilibrate for 20 minutesbefore the experiment was started. As a control, aconcentration-response curve for substance P obtained in the absence oftest compounds was used. The NK1 receptor antagonist activity of eachtest compound was determined by a concentration-response curve obtainedby pretreating at least three concentrations of the test compound for 10minutes and subsequently applying substance P in a cumulative manner.The Kb values were determined according to the method proposed by Schildand the results are shown in Table 1 (Schild Brit. J. Pharmacol. 14(1959): 49).

The composition of the Tyrode's solution was as follows: NaCl=136.9,KCl=2.7, CaCl₂.2H₂O=2.5, MgCl₂.6H₂O=1.0, NaH₂PO₄.2H₂O=0.4, NaHCO₃=11.9,glucose=11.1 (mmol/L) TABLE 1 Example Kb(nmol/L) 1 0.224 4 0.148 7 0.2108 0.275 9 0.0848 10 0.286 13 0.170

As can be seen from the results of Table 1, the compounds (1) or saltsthereof according to the invention prove to be effective NK1 receptorantagonists.

(2) Cystometry Test on Guinea Pigs

The method used was according to the method proposed by J S. Peterson etal. (Peterson J S. et al., J. Pharmacol. Methods 21 (1989): 231), towhich minor modifications were made.

Guinea pigs were anesthetized with halothane and the tenth thoracicspinal cord was cut in each animal. Subsequently, both ureters wereligated and were cut on the kidney-side. Polyethylene catheters wereinserted into the bladder to provide an injection pathway forphysiological saline and a pathway for the measurement of intravesicalpressure. Each animal was restricted in a Ballman cage and was left formore than 2 hours. Subsequently, room-temperature saline was injectedthrough the bladder catheter into the bladder at a rate of 6 mL/hr toconduct a cystometry test. After the effective bladder capacity wasstabilized, a test compound was intravenously administered from thejugular vein. The effective bladder capacity is defined as the volume ofsaline injected from one urination to the next. The effect of each testcompound was determined as the increase in the average bladder volume,which was determined by taking difference between the average bladdervolume measured 30 minutes prior to the administration of the testcompound and the average bladder volume measured every 30 minutes afterthe administration of the test compound. The results are shown in Table2. TABLE 2 Increase in Dose (i.v.) bladder capacity Test compounds mg/kg(%) Compound of Example 7 0.3 24.2 1 46.0 TAK-637* 0.3 12.0 1 23.8 320.5*Compound described in Example 18 in Japanese Patent Laid-OpenPublication No. Hei 9-263585

As can be inferred from the results of Table 2, the compounds (1) orsalts thereof according to the invention have a better ability toincrease the effective bladder capacity than TAK-637 in terms of theirpotency as well as their maximum effects.

Industrial Applicability

As set forth, the present invention has been devised based on thediscovery that the novel fused bicyclic pyridine derivatives and saltsthereof act as effective tachykinin receptor antagonists.

In particular, not only have the compounds of the present inventionproven to act as NK1 receptor antagonists, but they have also beenshown, by the Test Examples above, to have better effects than theconventional compounds.

Specifically, when the compounds of the present invention were testedfor their effects on dysuria, a tachykinin-mediated disorder, bycystometry, in which the ability of each of the compounds to increasethe effective bladder capacity was measured in guinea pigs with brokenspinal cords, they proved to have significantly higher pharmacologicaleffects as compared to TAK-637, a known compound. In brief, when givenin smaller doses, the compounds of the present invention exhibitedpharmacological effects comparable to the conventional. TAK-637compound. Also, the same doses of the compounds of the present inventionbrought about significantly better pharmacological effects and elicitedhigher maximum effects than TAK-637.

In addition, the compounds of the present invention and salts thereofexhibit little toxicity and are thus highly safe. Accordingly, thecompounds of the present invention and salts thereof, which areeffective tachykinin antagonists, are of significant usefulness in thetreatment of various pathological conditions including pollakiuria.

1. A fused bicyclic pyridine derivative represented by the followinggeneral formula (1), or a salt thereof: (General Formula (1))

wherein the rings A and B are each a benzene ring which may have 1 to 3substituents (any adjacent two of which may be bound to one another toform a ring) that are each independently selected from the groupconsisting of a halogen atom, a substituted or unsubstituted C₁ to C₆alkyl group, and a substituted or unsubstituted C₁ to C₆ alkoxy group;the ring C is a nitrogen-containing ring having a carbon atomsubstituted with a nitrogen atom; R¹ and R² are each independently ahydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆ alkylsulfonyl group, aC₁ to C₆ alkylcarbonyl group, or a C₁ to C₆ alkoxycarbonyl group, or R¹and R² are bound to one another to form the ring D, which is a 3- to7-membered non-aromatic heterocyclic ring that may contain, aside fromthe nitrogen atom, 1 to 3 heteroatoms selected from the group consistingof a nitrogen atom, a sulfur atom, and an oxygen atom and may furthercontain 1 or 2 oxo group-substituted carbon atoms; m is 1 or 2; n is 2or 3; and q is an integer from 1 to
 4. 2. A fused bicyclic pyridinederivative represented by the following general formula (1a), or a saltthereof: (General Formula (1a))

wherein R³ and R⁴ are each independently a hydrogen atom, a fluorineatom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethylgroup, a methoxy group, or a trifluoromethoxy group; the ring C is anitrogen-containing ring having a carbon atom substituted with anitrogen atom; R¹ and R² are each independently a hydrogen atom, a C₁ toC₆ alkyl group, a C₁ to C₆ alkylsulfonyl group, a C₁ to C₆ alkylcarbonylgroup, or a C₁ to C₆ alkoxycarbonyl group, or R¹ and R² are bound to oneanother to form the ring D, which is a 3- to 7-membered non-aromaticheterocyclic ring that may contain, aside from the nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom and may further contain 1 or 2 oxogroup-substituted carbon atoms; n is 2 or 3; and q is an integer from 1to
 4. 3. The fused bicyclic pyridine derivative according to claim 2 ora salt thereof, wherein in the general formula (1a), n is
 3. 4. Thefused bicyclic pyridine derivative according to claim 2 or a saltthereof, wherein in the general formula (1a), n is 3, and q in the ringC is
 3. 5. The fused bicyclic pyridine derivative according to claim 2or a salt thereof, wherein in the general formula (1a), n is 3, q in thering C is 3, and the ring D is represented by the following formula:

wherein p is an integer from 1 to 4, and X is an oxygen atom, a nitrogenatom, or a sulfur atom.
 6. The fused bicyclic pyridine derivativeaccording to claim 2 or a salt thereof, wherein in the general formula(1a), n is 3, q in the ring C is 3, and the ring D is represented by thefollowing formula:

wherein the ring D′ is a 3- to 7-membered cyclic amide that may contain,aside from the nitrogen atom, 1 to 3 heteroatoms selected from the groupconsisting of a nitrogen atom, a sulfur atom, and an oxygen atom.
 7. Thefused bicyclic pyridine derivative according to claim 2 or a saltthereof, wherein in the general formula (1a), n is 3, q in the ring C is3, and the ring D is represented by the following formula:


8. The fused bicyclic pyridine derivative according to claim 2 or a saltthereof, wherein in the general formula (1a), n is 3, q in the ring C is3, and R¹ and R² are each independently a hydrogen atom, a methyl group,an ethyl group, an acetyl group,
 9. The compound according to claim 2,wherein the compound represented by the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.10. The compound according to claim 2, wherein the compound representedby the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.
 11. The compound according to claim 2,wherein the compound represented by the general formula (1a) is5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine.12. A tachykinin receptor antagonist containing as an active ingredientthe fused bicyclic pyridine derivative according to claim 1 or a saltthereof.
 13. An NK1 receptor antagonist containing as an activeingredient the fused bicyclic pyridine derivative according to claim 1or a salt thereof.
 14. A prophylactic or therapeutic agent for dysuria,including defective bladder functions such as increased urinaryfrequency and incontinence of urine, containing as an active ingredientthe fused bicyclic pyridine derivative according to claim 1 or a saltthereof.
 15. A prophylactic or therapeutic agent for disorders ofdigestive tract such as ulcerative colitis and Crohn's disease,containing as an active ingredient the fused bicyclic pyridinederivative according to claim 1 or a salt thereof.
 16. A prophylactic ortherapeutic agent for vomiting induced by exposure to X-ray,chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs, containing as anactive ingredient the fused bicyclic pyridine derivative according toclaim 1 or a salt thereof.
 17. A therapeutic agent for treatingconditions, such as asthma, coughing, ache, migraine, tooth pain, andrheumatoid arthritis, containing as an active ingredient the fusedbicyclic pyridine derivative according to claim 1 or a salt thereof. 18.A tachykinin receptor antagonist containing as an active ingredient thefused bicyclic pyridine derivative according to claim 2 or a saltthereof.
 19. An NK1 receptor antagonist containing as an activeingredient the fused bicyclic pyridine derivative according to claim 2or a salt thereof.
 20. A prophylactic or therapeutic agent for dysuria,including defective bladder functions such as increased urinaryfrequency and incontinence of urine, containing as an active ingredientthe fused bicyclic pyridine derivative according to claim 2 or a saltthereof.
 21. A prophylactic or therapeutic agent for disorders ofdigestive tract such as ulcerative colitis and Crohn's disease,containing as an active ingredient the fused bicyclic pyridinederivative according to claim 2 or a salt thereof.
 22. A prophylactic ortherapeutic agent for vomiting induced by exposure to X-ray,chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs, containing as anactive ingredient the fused bicyclic pyridine derivative according toclaim 2 or a salt thereof.
 23. A therapeutic agent for treatingconditions, such as asthma, coughing, ache, migraine, tooth pain, andrheumatoid arthritis, containing as an active ingredient the fusedbicyclic pyridine derivative according to claim 2 or a salt thereof.